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Neuregulin Partner ErbB4 Spices Up Genetic Associations

17 February 2005. The last few years have seen a flurry of activity around neuregulin 1 (NRG1), with several studies finding or confirming that polymorphisms in the gene are linked to schizophrenia in Icelandic (see Stefannson et al., 2002; Williams et al., 2003), Irish (see Corvin et al., 2004), Chinese (see Yang et al., 2003), and Dutch (see Bakker et al., 2004) populations. But exactly how neuregulin 1 contributes to pathology is unclear. The protein is a large complex molecule involved in many biological activities, such as neuronal migration, synaptogenesis, myelination, and cell-to-cell communication. In the human brain, neuregulin 1 comes in as many as 15 different isoforms that may contain transmembrane, immunoglobulin, or epidermal growth factor (EGF) domains, to name just a few. While any or all of these motifs may be involved in schizophrenia pathology, the EGF domain may be particularly relevant (for review, see Harrison and Law, 2006 and SRF related meeting story). Two recent papers in the American Journal of Medical Genetics report that polymorphisms in the ErbB4 tyrosine kinase, a receptor for neuregulin’s EGF domain, are also linked to schizophrenia. In addition, a paper in PNAS explores the role of neuregulins and ErbB4 in neuronal differentiation and migration during adult neurogenesis.

Of ErbB4 SNPs and haps
In the January issue of the journal, Michael O’Donovan, Wales School of Medicine, Cardiff, and colleagues reported that a combination of specific polymorphisms in the neuregulin and ErbB4 genes increases susceptibility to schizophrenia. First author Nadine Norton and colleagues first sequenced the gene in DNA samples obtained from 14 unrelated patients to determine if there were any single nucleotide polymorphisms (SNPs) that could be linked to the disease. The researchers identified 15 SNPs. Two of these were in the coding regions of the gene, and the remaining 13 were found in flanking introns.

Norton and colleagues next tested over 600 patients and controls (unrelated Caucasians from the UK or Ireland) but found that there was no strong association between any of the 15 SNPs and schizophrenia. However, they did find that individuals who were heterozygous for one SNP (IVS12-15C>T) had a significantly higher risk for schizophrenia if they also tested positive for the so-called Icelandic neuregulin 1 haplotype—a combination of one SNP and two specific microsatellite sequences in the NRG1 gene. “Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with ErbB4,” write the authors.

The second paper published in the March edition of the journal, and currently available online, supports the neuregulin-ErbB4 connection. Ruth Navon from Tel Aviv University, Israel, and colleagues also set out to test if ErbB4 polymorphisms have any impact on the development of schizophrenia. First author Gilad Silberberg and colleagues selected nineteen ErbB4 SNPs from the human haplotype map database (see SRF related news story) and compared these sequences with those obtained from 59 Ashkenazi schizophrenia patients and 130 matched controls. They found that three of the SNPs, which are found in a block that encompasses exon 3, were differentially represented in the case and control samples. The results were highly significant and led the authors to conclude that neuregulin 1 and its receptor, ErbB4, are involved in the pathophysiology of schizophrenia.

Exciting as these findings may be, there is still the question of how the two genes conspire to increase the likelihood of developing the disease. Both research groups focused on expression of ErbB4 as a likely mechanism. Norton and colleagues used allelic expression assays, in which one allele of a heterozygote serves as an internal control for measuring the expression of the other, to determine expression levels of ErbB4 in 26 different individuals. They found that there was an almost twofold variation, suggesting that cis-acting polymorphisms may indeed regulate the expression of the protein in the human brain.

Silberberg and colleagues tried a slightly different approach, using real-time DNA amplification techniques to measure expression levels of specific isoforms. They found that ErbB4 containing either the cytoplasmic tail-1 (CYT-1) or the juxtamembrane-a (JM-a) domain was significantly elevated (1.8- and 1.3-fold, respectively) in dorsolateral prefrontal cortex samples taken from patients at postmortem. On the other hand, transcripts containing CYT-2 or JM-b domains were expressed at similar levels in patients and controls.

A developing story for schizophrenia?
If changes in expression of ErbB4 and or neuregulin can explain, even partly, the susceptibility to schizophrenia, the obvious question then becomes, what pathways and molecular interactions are perturbed by that overexpression (Harrison and Law, 2006)? One developmental interaction that may be particularly interesting was just reported by Eva Anton and colleagues in the February 7 PNAS. First author Troy Ghashghaei and colleagues report that neuregulins 1, 2, and ErbB4, play a role in the proliferation and migration of neural precursors in the subventricular zone (SVZ) of the brain. Examining the adult neurogenesis seen in the subventricular zone of mice, the researchers found that ErbB4 and the two neuregulins were robustly expressed in a variety of cells in the SVZ. While the receptor is mainly found on migratory neuroblasts, it also appears in astrocytes and ependymal cells. The authors found NRG2 in neuroblasts and a subset of astrocytes, though NRG1 was found almost exclusively in neuroblasts.

Figure1. In the photo on the left, normally migrating neuronal precursors form a bright green river flowing from the subventricular zone along the rostral migratory stream toward the olfactory bulb. In the next photo, application of neuregulin 1 has disrupted this stream. (Photo courtesy of Troy Ghashghaei, Eva Anton, and colleagues.)

To examine what role these proteins play in neurogenesis, the researchers added exogenous NRG1 or NRG2 to the SVZ of either wild-type animals or those that had the ErbB4 receptor knocked out. This allowed them to distinguish specific ErbB4-mediated action of the two neuregulins. They found that NRG1 stimulates aggregation of precursor cells and decreases neuroblast migration from the SVZ. NRG2, on the other hand, seems to stimulate proliferation and migration of neuroblasts and increases γ-aminobutyric acid neurons in the olfactory bulb. Examination of the cellular organization of the SVZ in the ErbB4-null mice showed that disrupting neuregulin-ErbB4 signaling disrupts different cell types in the SVZ, which may ultimately retard the generation and migration of neurons to their final destinations.

Figure 2. In the photo on the left, normal astrocyte processes stretch away from the ventricular surface, but in the next photo, from ErbB4-deficient mice, the fibers appear to have lost their way. (Photo courtesy of Troy Ghashghaei, Eva Anton, and colleagues.)

The fact that these three proteins may be involved in neuronal migration is of interest, given that schizophrenia is now widely believed to have a significant developmental component. In fact, Ghashghaei and colleagues posit that “abnormal NRG1 signaling in the SVZ and the resultant changes in neuroblast generation and placement may alter the neural circuitry of the brain and contribute to neurodevelopmental disorders such as schizophrenia.”—Tom Fagan.

References:
Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, Williams HJ, Preece AC, Swyer S, Wilkinson JC, Spurlock G, Kirov G, Buckland P, Waddington JL, Gill M, Corvin AP, Owen MJ, O’Donovan MC. Evidence that interaction between neuregulin 1 and its receptor ErbB4 increases susceptibility to schizophrenia. Amer. J. Med. Genet. Part B. February, 2006;141B:96-101. Abstract

Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R. The involvement of ErbB4 with schizophrenia: Association and expression studies. Amer. J. Med. Genet. Part B. February, 2006;141B:142-148. Abstract

Ghashghaei HT, Weber J, Pevny L, Schmid R, Schwab MH, Kent Lloyd KC, Eisenstat DD, Lai C, Anton ES. The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone. PNAS. February 7, 2006;103:1930-1935. Abstract

Comments on News and Primary Papers
Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 22 February 2006
Posted 22 February 2006
  I recommend the Primary Papers

The study of Ghashghaei and colleagues provides a remarkable insight into the function of neuregulin 1 (NRG1), and NRG2 in adult neurogenesis. The study demonstrates that NRG1(2)/ErbB4 signaling influences the proliferation, differentiation, organization, and migration of adult neural progenitor cells in the subventricular zone (SVZ) and rostral migratory stream (RMS), in a ligand- and cell-dependent fashion. Using immunohistochemistry, Ghashghaei and colleagues first demonstrate that NRG1, NRG2, and ErbB4 are expressed by distinct cell types in the SVZ and RMS, notably ErbB4 and NRG1 by polysialylated neural cell adhesion molecule positive (PSA-NCAM+) neuroblasts, and ErbB2/3/4 by a subset of GFAP+ cells. These observations extend the group's previous studies of NRG1 and ErbB4 in the RMS (Anton et al., 2004). In their current study, Ghashghaei went on to examine the effects of exogenous infusion of NRG1 and NRG2 on neurogenesis in the RMS of adult mice. Interestingly, NRG1 was shown to decrease the initiation of neuroblast migration from the SVZ to the RMS by inducing the rapid aggregation of cells in the SVZ. The consequence of this rise in NRG1 was a decrease in the number of PSA-NCAM+ cells in the RMS and GABA+ cells in the olfactory bulb, demonstrating that ectopic or elevated expression of NRG1 prevents differentiation and migration of neurons from the adult SVZ to the RMS.

The study is particularly interesting in terms of the role of NRG1/ErbB4 signaling in directional cell migration. Flames et al. (2004) recently reported that NRG1 (specifically the Ig containing family of isoforms, e.g., Types I, II and IV; for review, see Harrison and Law, 2006) functions as a long distance chemoattractant for ErbB4 positive GABAergic interneurons migrating from the medial ganglionic eminence to the developing cortex. The observation that NRG1 is a chemoattractant in other brain regions may appear somewhat contradictory to the findings of Ghashghaei, which suggest that in-vivo NRG1 actually inhibits migration of neurons from the SVZ (at least when introduced ectopically). However, it would seem that these two findings are actually consistent. Ghashghaei and colleagues ectopically infused NRG1 into the lateral ventricles of adult mice. The subsequent aggregation of cells in the SVZ demonstrates that NRG1 indeed acts as a chemoattractant, not in an obvious manner by inducing the cells to migrate away, but simply by "attracting" them to aggregate or "clump" where they are (subsequently preventing migration to the RMS). So in fact, both the studies of Flames and Ghashghaei show that NRG1 is chemotactic to specific populations of neurons and cells, whether it is expressed at a distance and cells preferentially migrate toward it, or in the immediate environment and cells are attracted to migrate to, or stay in its vicinity.

In the past few years, NRG1 and ErbB4 have both been identified as potential susceptibility genes for schizophrenia. The aim now is to determine the molecular and biological mechanisms by which the genes confer risk for the disease. In terms of schizophrenia, we have previously demonstrated that the Type I isoform of NRG1 is elevated in the hippocampus (and prefrontal cortex; see Hashimoto et al., 2004) in the disease and that expression of the novel Type IV isoform is related to disease-associated sequence variants within the NRG1 gene (Law et al., 2006). Furthermore, we have recently demonstrated that these changes are accompanied by altered expression of specific isoforms of the ErbB4 receptor, consistent with that of Silberberg et al., 2006 (Law et al., 2005). Ghashghaei and colleagues provide the first direct evidence that ectopic or elevated expression of NRG1 in the brain can perturb cell migration. In light of this and other evidence, our findings in schizophrenia may translate into altered neuronal migration, cortical development and possibly neurogenesis in the disease.

At present, the exact links between altered NRG1/ErbB4 signaling and the pathophysiology of schizophrenia are unknown and potentially numerous (i.e., synaptogenesis, neurotransmitter function, neuronal migration, differentiation, glia formation and function, myelination). Studies such as that of Ghashghaei et al. provide insight into the normal role of NRG1/ErbB4 signaling in neurodevelopment and the adult brain which is essential if we are to understand the pathogenic role of the NRG1 gene and its receptors in disease.

References:

Anton ES, Ghashghaei HT, Weber JL, McCann C, Fischer TM, Cheung ID, Gassmann M, Messing A, Klein R, Schwab MH, Lloyd KC, Lai C. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat Neurosci. 2004 Dec;7(12):1319-28. Epub 2004 Nov 7. Abstract

Flames N, Long JE, Garratt AN, Fischer TM, Gassmann M, Birchmeier C, Lai C, Rubenstein JL, Marin O. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron. 2004 Oct 14;44(2):251-61. Abstract

Hashimoto et al., 2004, Mol. Psychiatry 9, 299-307.

Law et al (a) 2006. Neuregulin 1 (NRG1) transcripts are differentially expressed in schizophrenia and regulated by 5’ SNPs associated with the disease. PNAS

Also See SfN 2005 SRF research news: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize

Law 2005, SNPing away at NRG1 and ErbB4 gene expression in schizophrenia Neuropsychopharmacology, vol. 30, Supplement 1.

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Comments on Related News


Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 22 April 2006
Posted 22 April 2006
  I recommend the Primary Papers

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Stephan Heckers, SRF Advisor
Submitted 29 April 2006
Posted 29 April 2006
  I recommend the Primary Papers

The gene Neuregulin 1 (NRG1) on chromosome 8p has been identified as one of the risk genes for schizophrenia. It is unclear how the DNA sequence variation linked to schizophrenia leads to abnormalities of mRNA expression. This would be important to know, in order to understand the downstream effects of the neuregulin gene on neuronal functioning in schizophrenia.

Law and colleagues explored this question in post-mortem specimens of the hippocampus of control subjects and patients with schizophrenia. This elegant study of the expression of four types of NRG1 mRNA (types I-IV) is exactly what we need to translate findings from the field of human genetics into the field of schizophrenia neuropathology. The findings are complex and cannot be translated easily into a model of neuregulin dysfunction in schizophrenia. I would like to highlight two findings.

First, the level of NRG1 type I mRNA expression was increased in the hippocampus of schizophrenia patients. This confirms an earlier study of NRG1 mRNA expression in schizophrenia. It remains to be seen how this change in NRG1 type I mRNA expression relates to the finer details of neuregulin dysfunction in schizophrenia.

Second, one single nucleotide polymorphism (SNP8NRG243177) of the risk haplotype linked to schizophrenia in earlier studies predicts NRG1 type IV mRNA expression. The SNP determines a binding site for transcription factors, providing clues for how DNA sequence variation may lead, via modulation of mRNA expression, to neuronal dysfunction in schizophrenia. It is exciting to see that we can now test specific hypotheses of molecular mechanisms in the brains of patients who have suffered from schizophrenia. The study by Law et al. is an encouraging step in the right direction.

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Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Bryan Roth, SRF Advisor
Submitted 5 May 2006
Posted 5 May 2006
  I recommend the Primary Papers

I think this is a very interesting and potentially significant paper. It is important to point out, however, that it deals with changes in mRNA abundance rather than alterations in neuregulin protein expression. No measures of isoform protein expression were performed, and it is conceivable that neuregulin isoform protein expression could be increased, decreased, or not changed. A second point is that although statistically significant changes in mRNA were measured, they are modest.

Finally, although multiple comparisons were performed, the authors chose not to perform Bonferroni corrections, noting in the primary paper that, "Correction for random effects, such as Bonferroni correction, would be an excessively conservative approach, particularly given that we have restricted our primary analyses to planned comparisons (based on strong prior clinical association and physical location of the SNPs) of four SNPs and a single haplotype comprised of these SNPs. Because the SNPs are in moderate LD, the degree of independence between markers is low and, therefore, correcting for multiple testing would result in a high type II error rate. The prior probability and the predictable association between the deCODE haplotype and expression of NRG1 isoforms (especially type IV, which is its immediate physical neighbor) combined with the LD between SNPs in this haplotype makes statistical correction for these comparisons inappropriate. Nevertheless, our finding regarding type IV expression and the deCODE haplotype and SNP8NRG243177 requires independent replication."

It will thus be important to determine if these changes in neuregulin mRNA isoform abundance are mirrored by significant changes in neuregulin isoform protein expression and if the findings can be independently replicated with other cohorts.

View all comments by Bryan Roth

Related News: Neuregulin, ErbB4 Drive Developmental Cell Fates

Comment by:  Cynthia Shannon Weickert, SRF AdvisorVictor Chong
Submitted 18 December 2006
Posted 18 December 2006

The study by Sardi et al. is truly remarkable. Their report of a novel ErbB4 cleavage-dependent mechanism regulating neuronal/astrocytic differentiation is groundbreaking, but their approach to unraveling and confirming this mechanism is more impressive. From their use of a yeast two-hybrid system in finding novel ErbB4 intracellular domain (E4ICD)-interacting factors to their meticulous experimental dissection of hypotheses and observations, the Corfas group has raised the bar in the investigation of mechanisms by which ErbB4 regulates neural precursor fates. In addition, the authors have shown that changes in E4ICD intracellular signaling pathways may produce cellular consequences distinct from those resulting from alterations in the activity of membrane-bound full-length ErbB4. More specifically, Sardi et al. illustrate that ErbB4 cleavage can regulate very early cell fates in the nervous system, while intact ErbB4 has mainly been examined in terms of its action at mature cortical synapses where its activation can dampen NMDA receptor function.

Recognition must also be given to Pat McCaffrey and Hakon Heimer, who provided an excellent summary of the article and highlighted the significance of the paper to schizophrenia. In the manuscript, disruptions in E4ICD signaling are discussed in terms of their relevance to Alzheimer disease. Since aberrant neuregulin-1-ErbB4 signaling has been implicated in schizophrenia, one could hypothesize that alterations in E4ICD-associated interactions and/or in the nuclear translocation of E4ICD complexes may contribute to schizophrenia pathology as well. Hence, it will be important to test whether either or both of these ErbB4-signaling streams are in fact altered not only in Alzheimer disease, but also in schizophrenia.

The difficulty in linking ErbB4 to neuropathological mechanisms underlying schizophrenia may be due in part to the limited information that exists on early developmental processes of this illness. In their paper, Sardi et al. suggest disruptions in ErbB4-dependent mechanisms may lead to premature astrogenesis that could contribute to Alzheimer disease-associated gliosis. However, in thinking about the relevance of altered E4ICD signaling in schizophrenia, elevated glial formation has not been observed in the schizophrenic brain. In fact, expression of the glial marker, GFAP, has been shown to be reduced in postmortem brains of subjects with this disorder (Johnston-Wilson et al., 2000; Webster et al., 2005). On the other hand, recent investigations suggest elevated prefrontal cortical feed-forward neuregulin-1-ErbB4 signaling in schizophrenia (Hahn et al., 2006), and this increase could lead to GFAP reductions possibly through the mechanism proposed by Sardi et al. if this elevated signaling translated to greater E4ICD cleavage. However, whether the findings of Sardi et al. in neural precursor cells extend to cells of the adult human brain remains to be explored. Nevertheless, the Corfas group has opened new avenues of research in the field of schizophrenia and has provided a framework for future studies on the role ErbB4 signaling in this disease.

References:

Johnston-Wilson N.L., Sims C.D., Hofmann J.-P., Anderson L., Shore A.D., Torrey E.F. and Yolken R.H. (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol. Psychiatry. 5: 142-149. Abstract

Webster M.J., O'Grady J., Kleinman J.E. and Weickert C.S. (2005) Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. Neuroscience. 133: 453-461. Abstract

Hahn C.G., Wang H.Y., Cho D.S., Talbot K., Gur R.E., Berrettini W.H., Bakshi K., Kamins J., Borgmann-Winter K.E., Siegel S.J., Gallop R.J., Arnold S.E. (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12: 824-828. Abstract

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Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Patricia Estani
Submitted 9 June 2007
Posted 10 June 2007
  I recommend the Primary Papers

Related News: Down to BACE-ics—Old Mouse a New Model for Schizophrenia?

Comment by:  Victor ChongCynthia Shannon Weickert (SRF Advisor)
Submitted 23 May 2008
Posted 23 May 2008

The findings of Savonenko et al. (2008) are an impressive addition to the growing evidence supporting a role for neuregulin-1 (NRG1) in schizophrenia pathology. The authors not only revealed a novel relationship between schizophrenia-like behavior and the loss of BACE1 proteolytic function, but also showed that this association results from disruption of BACE1-mediated NRG1 cleavage. These observations support the notion that aberrant processing of NRG1 may contribute to the development of schizophrenia-like phenotypes, providing a basis for examining other NRG1-cleaving pathways in the context of schizophrenia. Savonenko et al. were thorough in their behavioral assessment of the BACE1 mutant mice, convincingly showing that these animals exhibit schizophrenia-related behaviors that could be exacerbated by psychostimulants and improved by antipsychotic drug treatment.

What remains unclear, however, is the relationship between the NRG1/ErbB4 protein findings in the BACE1 mutant mouse brain and those previously reported in the schizophrenic human brain. For example, the authors reported reductions in ErbB4-PSD95 coupling in the BACE1 mutant mouse, whereas Hahn et al. (2006) demonstrated increased ErbB4-PSD95 interaction in the prefrontal cortices of schizophrenic patients. In addition, our recent investigation found elevated prefrontal cortical levels of both NRG1 C-terminal fragment (ICD) and full-length ErbB4 protein in schizophrenic subjects (Chong et al., 2008), while Savonenko et al. showed decreased NRG1 C-terminal fragment levels with no alterations in ErbB4 protein in the BACE1 mutant mouse cortex. On the other hand, the lack of variations in overall cortical ErbB4 in these mice may correspond to the findings of Hahn et al. (2006) who reported no alterations in prefrontal cortical ErbB4 protein levels in schizophrenic subjects.

These seemingly conflicting results could suggest that any imbalance in cortical NRG1 signaling, whether increased or diminished, may lead to schizophrenia. Indeed, studies have suggested that improper tuning of other cortical signaling systems, particularly those of dopamine, can contribute to cognitive deficits associated with this disease (Vijayraghavan et. al, 2007). Optimal synaptic function may display “inverted-U” shaped response to NRG1-ErbB4 activity as proposed by Role and Talmage (2007). Alternatively, the authors speculated that some of the discrepancies between the findings in the BACE1 mutant mice and those observed in the schizophrenic humans may be due to differences in the duration of NRG1 signaling modification between the animals and the patients, who had a lifetime of mental illness. One way to examine the validity of this suggestion is to look at cortical ErbB4-PSD95 coupling and NRG1/ErbB4 protein levels in the BACE1 mutant mice at different developmental and adult time points. This approach could test whether these animals at later stages in life display alterations in cortical ErbB4-PSD95 interactions and/or in NRG1/ErbB4 protein levels comparable to those seen in schizophrenic subjects of the human studies, which primarily consisted of adults beyond middle age. Also of interest would be to create NRG1 and ErbB4 gain-of-function mutants where the timing of over-expression could be controlled.

Given the significance of NRG1 signaling/cleavage in the BACE1 mutant mouse schizophrenia-like phenotypes, it may also be important to consider pathways leading to changes in ErbB4 C-terminal fragment levels in schizophrenia etiology. A recent paper by Walsh et al. (2008) demonstrated that at least one schizophrenic patient in their study has a gene deletion encompassing the C-terminal intracellular kinase domain of ErbB4, and we have found decreases in ErbB4 C-terminal fragments relative to full-length ErbB4 in the frontal cortex of schizophrenic subjects (Chong et al., 2008). These observations together with those of Savonenko et al. raise interesting questions regarding how molecular alterations in NRG1 signaling and cleavage may impact ErbB4 signaling and cleavage and whether changes in NRG1 and/or ErbB4 could be primary or secondary to the schizophrenia disease process.

In summary, Savonenko et al. have provided a novel avenue to probe NRG1 function and processing in relation to schizophrenia pathology. They have also introduced BACE1 as a potentially important schizophrenia susceptibility molecule that to our knowledge has not been directly investigated in subjects with schizophrenia and may be worth studying in the brain tissues of these patients. In addition, it would be interesting to examine how the schizophrenia-related traits of the BACE1 mutant mice compare with those of other NRG1 mutant mice such as the heterozygous NRG1 transmembrane knock-out mice (Stefansson et al., 2002). Such an investigation could provide insight into whether similar NRG1 signaling deficiencies underlie the schizophrenia-like phenotypes of these animal models.

References:

Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med. 12:824-8. Abstract

Chong VZ, Thompson M, Beltaifa S, Webster MJ, Law AJ, Weickert CS. (2008) Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. Schizophr Res. 100:270-80. Abstract

Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 10:376-84. Abstract

Role LW, Talmage DA (2007) Neurobiology: new order for thought disorders. Nature. 448:263-5. Abstract

Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 320:539-43. Abstract

Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K. (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 71:877-92. Abstract

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Related News: Unkind Cuts of NRG3 May Lead to Schizophrenia

Comment by:  Assen Jablensky
Submitted 15 September 2010
Posted 15 September 2010

Common or rare genetic variation in NRG3 influences risk for schizophrenia?
Emerging evidence implicating NRG3 as a likely susceptibility gene in population samples as diverse as the Ashkenazi Jews, Han Chinese, Australians of Anglo-Irish ancestry, and white Americans is certainly a “noteworthy” occurrence in schizophrenia genetics. The latest addition to the evidence (Kao et al., 2010) provides considerable support to earlier (Fallin et al., 2003; Wang et al., 2008) and recent findings of association of several polymorphisms (rs10883866, rs6584400, rs10748842) within a conserved linkage disequilibrium (LD) block in intron 1 of the NRG3 gene with a delusion-laden factor and a neurocognitive quantitative trait in the schizophrenia phenotype (Chen et al., 2009; Morar et al., 2010).

A fundamental contribution of the present study is the cloning and detailed characterization of full-length NRG3 transcripts from postmortem fetal, child, adolescent, and adult brain samples (whole brain, hippocampus, and dorsolateral prefrontal cortex). Sequencing of the cDNA clones and expression analysis revealed a complex picture of alternative splicing, abundance of developmentally regulated transcripts in schizophrenia brains, and, notably, increased expression of a fetal brain-derived clone (hFBNRG3), which introduces a premature stop codon resulting in a truncated protein and a possibly destabilized NRG3-ErbB4 signalling pathway. In their clinical collections (a family-based sample and a partially independent case-control sample), the authors report significant associations of rs10748842 (representing 12 SNPs located in the LD block within intron 1) with schizophrenia, with the PANSS (Positive and Negative Syndrome Scale) subscale score on delusion severity, as well as with the PANSS negative symptom load.

Overall, the findings from this investigation and the earlier studies appear to be in a broad agreement, converging on a plausible role of NRG3 in schizophrenia pathogenesis. However, there is a fly in the ointment: The associations found in the present study exhibit a risk allele reversal compared to previously reported results; namely, all significant associations are with the major, common alleles, rather than with the minor alleles, as in Chen et al. (2009) and Morar et al. (2010). While many reasons for genuine allele flipping can be invoked (multi-locus interactions, variation in local patterns of LD, environmental exposures, ethnic background differences—see Clarke and Cardon, 2010), the explanation for the flip in this particular context is not obvious, and NRG3 should remain on the examination bench. Even in the GWAS era, studies proceeding from biologically and clinically anchored hypotheses remain rewarding and potentially productive.

References:

Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang K-Y, Nestadt G, Feng N, Steel G, Cutting AS, Wolyniec P, Pulver AE, Valle D. Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet. 2009;84:21-34. Abstract

Clarke GM, Cardon LR. Aspects of observing and claiming allele flips in association studies. Genet Epidemiol. 2010;34:266-74. Abstract

Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet. 2003;73:601-11. Abstract

Kao WT, Wang Y, Kleinman JE, Lipska BK, Hyde TM, Weinberger DR, Law AJ. Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15619-24. Abstract

Morar B, Dragovic M, Waters FAV, Chandler D, Kalaydjieva L, Jablensky A. Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry. 2010 June 15. Abstract

Wang YC, Chen JY, Chen ML, Chen CH, Lai IC, Chen TT, Hong CJ, Tsai SJ, Liou YL. Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry. 2008;64:1093-6. Abstract

View all comments by Assen Jablensky